P1 - AG Hansen/ Buer Anne Günther

P01: Impact of the sphingomyelin/ceramide pathway on immune cell function

Sphingolipids are bioactive molecules with various functions. Beside their importance in cell integrity as structural components of the plasma membrane, they are proposed to regulate different physiological and pathophysiological cellular processes. By generating and hydrolysing ceramide, acid sphingomyelinase (ASM) and acid ceramidase (AC) are two key players in the complex metabolic network of sphingolipids.

Previous studies revealed that tumor cell lines implanted in ASM-deficient mice showed a double growth rate as compared to their growth rate in wild-type mice and that these tumors are resistant to radiotherapy. Within this project we could demonstrate less activation of tumor-infiltrating T cells in ASM-deficient mice and that T cell specific overexpression of ASM leads to a reduction in tumor growth. To further clarify the role of accumulating ceramide on activation and function of T cells during tumorigenesis, we aim to modulate the ceramide pathway by systemic and cell type specific ablation of AC expression.

There is also growing evidence that sphingolipids play a crucial role in infectious diseases. Ceramide and its metabolites have been shown to be involved in the internalization of pathogens, the induction of apoptosis in infected cells and the regulation of cellular signalling processes, rendering sphingolipids to be promising targets for therapeutic purposes. Indeed, we could show that T cell specific overexpression of ASM in mice is protective in malaria infection. Using global and cell type specific AC ko mice, we aim to further investigate how sphingolipids modulate the course of infection and the function of different immune cells during Plasmodium infection.